Lead Investigator: Dr Richard Killick
Institution: King's College London
Grant type: Project
Duration: 3 years, 4 months
Start Date: October 2010
Completion Date: March 2014
Scientific Title: Uncovering the molecular mechanism of the amyloid cascade: p53 as a central component.
What was the project, and what did the researchers do?
Alzheimer’s disease is characterised by the presence of two proteins, called amyloid and tau, which form clumps that are harmful to brain cells. Scientists currently believe that the amyloid protein clumps are produced first; this then triggers the accumulation of tau. However, the mechanism behind this process is not yet understood.
Dr Killick and his colleagues used this project to investigate the relationship between amyloid and tau, and to uncover the molecular mechanisms in cells that link them together. In order to do this, they used various techniques to measure the activity of proteins in the cells grown in the lab. The researchers also focused on finding any potential treatments that would interfere with this relationship in order to prevent Alzheimer’s disease from progressing.
What were the key results, and how will this help in the fight against dementia?
The researchers were able to identify steps linking the amyloid protein to the disruption of connections between brain cells, a key aspect of Alzheimer’s disease. They also uncovered a role for the Alzheimer’s risk gene clusterin, discovering that it could influence the function of the amyloid protein. The effect of amyloid on clusterin led to a series of complex molecular stages that caused harm to the brain cells grown in the lab.
This research helps us to understand the process behind why the amyloid protein can be harmful to brain cells. Along with clusterin, the researchers also uncovered potential roles for the gene with the strongest known link to non-inherited Alzheimer’s, which is called ApoE. This knowledge will help to identify potential targets for the development of treatments for the condition.
Dr Killick and his colleagues have already begun trying to identify molecules that can interfere with these processes. This includes looking at existing drugs for other conditions and investigating whether they could be used to treat Alzheimer’s. This is known as drug repurposing and is a key aspect of our drug discovery programme.
What happened next? Future work and additional grants
Dr Killick and his collaborator on this project, Dr Simon Lovestone, have been awarded a further grant from Alzheimer’s Society to continue investigating this pathway. They will use innovative methods to find potential new Alzheimer’s disease treatments that target the molecular mechanisms that they have discovered can link amyloid to tau.
The investigators were also awarded funds from the Guy’s and St Thomas’s Charity to try and find new drugs that target one of the proteins involved in this pathway. They found several potential new treatments during this project, which they are hoping to investigate further.
How were people told about the results? Conferences and publications
Killick, R. et al. (2014) Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol Psychiatry 19, 88-98, doi:10.1038/mp.2012.163.
ARUK meeting, 2014